CN113509448A - Biodegradable controlled-release long-acting implant tablet and preparation method thereof - Google Patents
Biodegradable controlled-release long-acting implant tablet and preparation method thereof Download PDFInfo
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- CN113509448A CN113509448A CN202010643090.1A CN202010643090A CN113509448A CN 113509448 A CN113509448 A CN 113509448A CN 202010643090 A CN202010643090 A CN 202010643090A CN 113509448 A CN113509448 A CN 113509448A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
Abstract
The invention relates to a biodegradable controlled-release long-acting implant tablet and a preparation method thereof, belonging to the technical field of medicines, wherein the biodegradable controlled-release long-acting implant tablet consists of levonorgestrel, polylactic acid-glycolic acid copolymer and polycaprolactone; the preparation method comprises the steps of preparing microspheres with the grain diameter of 3 mu m by an emulsification-solvent volatilization method, and preparing the microspheres into implant tablets with the diameter of 6mm by direct tabletting and coating controlled release film. By utilizing the sustained release characteristic of the microspheres and the controlled release characteristic of the controlled release membrane, the levonorgestrel is slowly released at a constant rate, the release time can reach 90 days, the levonorgestrel clinically administered drug has good biocompatibility and biodegradability, the carrier material is not required to be taken out by a secondary operation, the blood concentration in vivo is stable, and the adverse reaction is less.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a biodegradable controlled-release long-acting implant tablet and a preparation method thereof. The implant sheet has good biocompatibility and biodegradability, can slowly and continuously release the medicine in vivo to play a contraceptive effect, and can take out blank carrier materials without operation after the medicine is completely released.
Background
Accidental pregnancy and repeated miscarriages are global problems. About 2000 thousands of women are unexpectedly pregnant each year, with one-fourth of them choosing to artificially terminate pregnancy, and the main reason for this phenomenon is that contraceptive methods are not used properly or correctly. In recent years, China actively adjusts the birth control policy for many times, so higher requirements are put forward on the reproductive health of women of childbearing age and the modes of contraception and birth control. This means that the development of diverse contraceptive products is currently the most major requirement and public health problem.
Levonorgestrel (LNG) is a potent progestational hormone contraceptive which is the most widely used internationally, and mainly interferes with the function of hypothalamus-pituitary-ovary to exert contraceptive effect. Has effects of inhibiting ovulation, thickening cervical mucus, and preventing sperm penetration by interfering menstrual cycle.
The subcutaneous contraceptive implant is prepared by preparing a contraceptive medicament and a macromolecular carrier into a subcutaneous implant preparation. The drug is released by the carrier, absorbed into blood by subcutaneous capillaries, and can maintain effective contraceptive concentration for a long time in vivo, thereby playing the contraceptive effect. The drug delivery system can avoid the first pass effect of liver metabolism, improve the bioavailability of the drug, and is a long-acting, efficient and safe contraception mode. Is suitable for most women of childbearing age. However, the LNG subcutaneous implant taking the silicon rubber as the carrier is not degradable in vivo, and needs to be taken out by a professional in a medical institution after the drug release is finished. The silicone rubber is easy to age after long-term administration in vivo, and the taking-out difficulty is increased, so that secondary injury can be brought to women of childbearing age.
Disclosure of Invention
The invention aims to provide a biodegradable controlled-release long-acting implant and a preparation method thereof. The prepared levonorgestrel implant tablet has obvious sustained and controlled release effect and can maintain effective contraceptive concentration for a long time in vivo; the selected material has good biocompatibility and biodegradability, can not cause inflammatory reaction of in vivo tissues, and the carrier material can be automatically degraded in vivo after the drug release is finished, so that a blank carrier is not required to be taken out in a secondary operation.
The levonorgestrel is widely used for meeting the contraceptive requirements of women of childbearing age, and the applicant compresses drug-loaded microspheres into tablets on the basis of preparing the microspheres by an O/W emulsification-solvent volatilization method, wraps the tablets with a rate controlled release film to obtain the levonorgestrel sustained-release implant tablet, and inspects the in-vitro release result of the levonorgestrel sustained-release implant tablet.
In order to realize the task, the invention is realized by the following technical scheme:
a biodegradable controlled release long-acting implant and a preparation method thereof are characterized by comprising the following components: the progestin levonorgestrel and biodegradable polymeric materials.
The biodegradable polymer is selected from the following three types:
(a) and polylactic acid-glycolic acid copolymer (PLGA), wherein the ratio of polylactic acid to glycolic acid is 50: 50 or 75: 25, and the molecular weight is 20000-30000.
(b) And Polycaprolactone (PCL) with the molecular weight of 10000-30000.
The weight percentage of the levonorgestrel in the biodegradable controlled-release long-acting implant tablet is 3.8-15.6% (w/w).
The biodegradable controlled-release long-acting implant tablet comprises the biodegradable polymer in an amount of 84.4.4-96.2% (w/w) by mass.
The biodegradable controlled-release long-acting implant is a long-acting contraceptive round tablet for subcutaneous implantation.
The preparation method of the biodegradable controlled-release long-acting implant is characterized by comprising the following steps of:
1. preparation of aqueous polyvinyl alcohol (PVA) solution:
adding one or more of polyvinyl alcohol-124 and polyvinyl alcohol-1788 into the water solution, swelling for 2 hours, heating for enough time under the condition of water bath to dissolve completely, preparing the water solution of polyvinyl alcohol (PVA) with the concentration of 0.5-3%, and cooling to room temperature;
2. preparing a drug-containing oil phase:
adding a proper amount of ethyl acetate, tetrahydrofuran, dichloromethane, trichloromethane, acetone or a mixture of two or more solvents into polylactic acid-glycolic acid copolymers with different weight ratios to prepare a solution with the concentration of 5 mg/mL-20 mg/mL, adding 3.8-7.6% (w/w) of levonorgestrel raw material medicine, sealing, and completely dissolving by ultrasonic waves;
3. preparing biodegradable drug-loaded microspheres:
the medicine carrying microsphere is prepared by adopting an O/W emulsification-solvent volatilization method. Slowly dripping the oil phase containing the medicine into a polyvinyl alcohol (PVA) aqueous solution by using an injector, and carrying out ultrasonic emulsification in an ultrasonic emulsifier for 2-5 minutes (setting engineering parameters of ultrasonic on-time 2 seconds, ultrasonic off-time 2 seconds and alarm temperature 40.0 ℃) to obtain O/W colostrum. Stirring or rotary evaporation is adopted to volatilize the organic solvent, and the microspheres are solidified. Then, carrying out centrifugal water washing to remove free drugs on the surface, and carrying out freeze drying for 24-48 hours to obtain drug-loaded microsphere freeze-dried powder;
4. tablet core pressing:
pressing the drug-loaded microspheres by using a single-punch tablet press to obtain a tablet core with the diameter of 6mm, wherein the tablet weight is 73.07-84.93 mg, and the ratio of the tablet thickness to the tablet diameter is 1: 3; the hardness is 2-3 kg;
5. preparing a controlled-release coating solution:
dissolving a proper amount of polycaprolactone by using acetone, dichloromethane, trichloromethane or a mixture of two or more solvents to prepare a solution with the concentration of 2-6%, and sealing;
6. coating of the implant: and coating the tablet core with a polycaprolactone controlled-release film, wherein the coating weight is increased by 3-5%, so as to obtain the levonorgestrel controlled-release long-acting implant tablet.
The invention relates to a biodegradable controlled-release long-acting implant and a preparation method thereof. Is a long-acting contraceptive tablet for subcutaneous implantation, and after being implanted into the body, the levonorgestrel is slowly released at a certain rate. The selected polycaprolactone and polylactic acid-glycolic acid copolymer can be degraded in vivo into normal metabolites of carbon dioxide and water in vivo, and are discharged out of the body, so that the polycaprolactone and polylactic acid-glycolic acid copolymer has good biocompatibility and degradation characteristics, and a series of defects caused by secondary operation taking out are avoided. The release time of the levonorgestrel can be controlled between 30 days and 90 days, and the effective contraceptive concentration can be maintained for a long time.
Drawings
FIG. 1 is a graph showing the release profile of the coated controlled release film solutions at different concentration rates in an implant
FIG. 2 graph of blood concentration versus time
Detailed Description
Biodegradable controlled-release long-acting implant tablet and preparation method thereof
A biodegradable controlled release long-acting implant and a preparation method thereof are disclosed, which comprises the following components: drugs and biodegradable polymeric materials. The biodegradable polymer is selected from the following group:
(a) and polylactic-co-glycolic acid (PLGA) with a monomer ratio of 50: 50 or 75: 25 and a molecular weight of 20000-30000.
(b) And Polycaprolactone (PCL) with the molecular weight of 10000-30000.
In the following embodiments, the preferred weight ratio of each raw material component is: medicine preparation: 3.8-7.6% (w/w), polylactic acid-glycolic acid copolymer: 92.4-96.2% (w/w), the sum of the weight percentages of the components is 100%.
The preparation method comprises the following steps:
1. preparation of aqueous polyvinyl alcohol (PVA) solution:
adding a proper amount of polyvinyl alcohol (PVA) into the aqueous solution, heating for a sufficient time under the condition of water bath after full swelling to completely dissolve the PVA to prepare 0.5-3% polyvinyl alcohol (PVA) aqueous solution, taking out and cooling to room temperature;
2. biodegradable drug-loaded polymer-dichloromethane (CH)2Cl2) Preparation of the solution:
weighing polylactic acid-glycolic acid copolymer with different weight ratios, adding proper amount of dichloromethane (CH)2Cl2) Preparing a solution with the concentration of 5 mg/mL-20 mg/mL, adding 3.8-7.6% (w/w) of the levonorgestrel bulk drug, sealing and ultrasonically dissolving;
3. preparing drug-loaded microspheres:
the medicine carrying microsphere is prepared by adopting an O/W emulsification-solvent volatilization method. Slowly dripping the drug-containing oil phase into the polyvinyl alcohol aqueous solution by using an injector, and carrying out ultrasonic emulsification in an ultrasonic emulsifier for 2-5 minutes at the temperature of 40.0 ℃ to obtain O/W primary emulsion. Stirring or rotary evaporation is adopted to volatilize the organic solvent, and the microspheres are solidified. Then, carrying out centrifugal water washing to remove free drugs on the surface, and carrying out freeze drying for 24-48 hours to obtain drug-loaded microsphere freeze-dried powder;
4. tablet core pressing:
pressing the drug-loaded microspheres by using a single-punch tablet press to obtain a tablet core with the diameter of 6mm, wherein the tablet weight is 73.07-84.93 mg, and the ratio of the tablet thickness to the tablet diameter is 1: 3; the hardness is 2-3 kg;
5. preparing a controlled-release coating solution:
dissolving appropriate amount of polycaprolactone with acetone, dichloromethane, chloroform or mixture of two or more solvents; preparing polycaprolactone coating solutions with different concentrations (2%, 3%, 4%, 5% and 6%) and sealing.
6. Coating of the implant:
and (3) coating the tablet core with polycaprolactone controlled-release films with different concentrations to increase the weight by 3-5% to obtain the levonorgestrel implant tablet.
Polylactic acid-glycolic acid copolymer (PLGA) is formed by random polymerization of monomer lactic acid and glycolic acid, and the final product is carbon dioxide and water, is safe and non-toxic, has good biocompatibility and film-forming and capsule-forming characteristics, and is approved by FDA to be applied to microcapsules for medical injection, microspheres and raw materials of tissue engineering implants.
Polycaprolactone (PCL) has good biocompatibility and biodegradability, can be used as a rate controlled release membrane to control the release of drugs in a subcutaneous implant, and has been widely used in drug controlled release systems.
The preparation of the levonorgestrel microsphere by an emulsion solvent volatilization method basically comprises 4 steps: adding medicine, forming emulsion drops, removing solvent and drying and recovering microspheres. The O/W solvent evaporation method is commonly used for encapsulating liposoluble drugs, and comprises the steps of dissolving and mixing the drugs and carrier materials, emulsifying the mixture with a water phase, after the system is stable, adopting continuous stirring or reduced pressure extraction and other methods to enable an organic solvent to be diffused into a continuous phase, evaporating the organic solvent to gradually solidify microspheres, and finally carrying out filtration, cleaning, drying and other operations to obtain the drug-carrying microspheres. The method is simple in design and safe and feasible in operation.
Example 1
1. Adding a proper amount of polyvinyl alcohol (PVA) into the aqueous solution, heating for a sufficient time under the condition of water bath after full swelling to completely dissolve the PVA to prepare 0.5-3% polyvinyl alcohol (PVA) aqueous solution, taking out and cooling to room temperature;
2. respectively putting polymer polylactic acid-glycolic acid copolymer (PLGA, molecular weight is 20000, ratio of lactic acid to glycolic acid is 75: 25 and 50: 50) into different containers, adding certain amount of dichloromethane (CH)2Cl2) Sealing and ultrasonic dissolving to obtain a solution with a certain concentration (5 mg/mL-20 mg/mL); adding 3.8-15.6% (w/w) of levonorgestrel raw material medicine, sealing and ultrasonically dissolving;
3. preparing the drug-loaded microspheres by adopting an O/W emulsification-solvent volatilization method, namely slowly dripping the drug-containing oil phase in the step 2 into the polyvinyl alcohol aqueous solution with a certain concentration in the step 1) by using an injector, carrying out ultrasonic emulsification for 2 minutes, magnetically stirring the suspension at room temperature, and volatilizing the organic solvent.
4. After centrifuging the suspension from which dichloromethane has been evaporated for 10 minutes at 12000r/min, the supernatant is discarded, the above operation is repeated 3 times with distilled water, and the microspheres are washed. Drying for 48 hours by using a freeze dryer, and collecting the microsphere freeze-dried powder to obtain the following 2 levonorgestrel slow-release microspheres:
(A) 4mg of levonorgestrel and 60mg of polylactic-co-glycolic acid (PLGA, 75: 25).
(B) 4mg of levonorgestrel and 60mg of polylactic-co-glycolic acid (PLGA, 50: 50).
The 2 levonorgestrel microspheres obtained in example 1 are respectively placed in a constant-temperature water bath shaking table, and the cumulative release amount (%) of the drug at different time points is determined, so that the release speed of the (B) is found to be fast, and is 15-30 days. (A) The release rate of (a) is relatively slow, more than 60 days.
Example 2:
1. adding a proper amount of polyvinyl alcohol (PVA) into the aqueous solution, heating for a sufficient time under the condition of water bath after full swelling to completely dissolve the PVA to prepare 0.5-3% polyvinyl alcohol (PVA) aqueous solution, taking out and cooling to room temperature;
2. respectively putting polymer polylactic acid-glycolic acid copolymer (PLGA, molecular weight is 20000, ratio of lactic acid to glycolic acid is 75: 25) into different containers, adding certain amount of dichloromethane (CH)2Cl2) Sealing and ultrasonic dissolving to obtain a solution with a certain concentration (5 mg/mL-20 mg/mL); adding 3.8-15.6% (w/w) of levonorgestrel raw material medicine, sealing and ultrasonically dissolving;
3. preparing the drug-loaded microspheres by adopting an O/W emulsification-solvent volatilization method, namely slowly dripping the drug-containing oil phase in the step 2 into the polyvinyl alcohol aqueous solution with a certain concentration in the step 1) by using an injector, carrying out ultrasonic emulsification for 2 minutes, magnetically stirring the suspension at room temperature, and volatilizing the organic solvent.
4. Centrifuging the suspension with dichloromethane evaporated at 12000r/min for 10min, discarding supernatant, repeating the above operation with distilled water for 3 times, and washing the microspheres. And drying for 48 hours by using a freeze dryer, and collecting the microsphere freeze-dried powder to obtain the following 5 levonorgestrel slow-release microspheres.
(A) 3mg of levonorgestrel and 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25).
(B) 4mg of levonorgestrel and 60mg of polylactic-co-glycolic acid (PLGA, 75: 25).
(C) 4.62mg of levonorgestrel and 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25).
(D) 5.45mg of levonorgestrel and 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25).
(E) 6mg of levonorgestrel and 60mg of polylactic-co-glycolic acid (PLGA, 75: 25).
The 5 levonorgestrel microspheres obtained in example 2 are respectively placed in a constant-temperature water bath shaking table, and the cumulative release amount (%) of the drugs at different time points is determined, so that the release speeds of (A), (B) and (C) are high and are 30-45 days, the release speed of (D) can reach 60 days, and the release speed of (E) is low and is 70 days.
Example 3:
1. adding a proper amount of polyvinyl alcohol (PVA) into the aqueous solution, heating for a sufficient time under the condition of water bath after full swelling to completely dissolve the PVA to prepare 0.5-3% polyvinyl alcohol (PVA) aqueous solution, taking out and cooling to room temperature;
2. respectively putting polymer polylactic acid-glycolic acid copolymer (PLGA, molecular weight is 20000, and ratio of lactic acid to glycolic acid is 85: 15, 75: 25 and 50: 50) into different containers, adding certain amount of dichloromethane (CH)2Cl2) Sealing and ultrasonic dissolving to obtain a solution with a certain concentration (5 mg/mL-20 mg/mL); adding 3.8-15.6% (w/w) of levonorgestrel raw material medicine, sealing and ultrasonically dissolving;
3. preparing the drug-loaded microspheres by adopting an O/W emulsification-solvent volatilization method, namely slowly dripping the drug-containing oil phase in the step 2 into the polyvinyl alcohol aqueous solution with a certain concentration in the step 1 by using an injector, carrying out ultrasonic emulsification for 2 minutes, magnetically stirring the suspension at room temperature, and volatilizing the organic solvent.
4. Centrifuging the suspension with dichloromethane evaporated at 12000r/min for 10min, discarding supernatant, repeating the above operation with distilled water for 3 times, and washing the microspheres. And drying for 48 hours by using a freeze dryer, and collecting the microsphere freeze-dried powder to obtain the following 5 levonorgestrel slow-release microspheres.
5. And tabletting the obtained levonorgestrel microspheres by using a single-punch tablet machine under certain pressure to obtain the levonorgestrel implant tablets with the diameter of 6 mm.
6. Coating the levonorgestrel implant tablet obtained by pressing with polycaprolactone controlled-release membrane solutions with different concentrations (2-6%) to obtain the following 6 levonorgestrel sustained-release implant tablets.
(A) 5.45mg of levonorgestrel and 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25).
(B) 5.45mg of levonorgestrel, 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25) and 0.10g of Polycaprolactone (PCL).
(C) 5.45mg of levonorgestrel, 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25) and 0.15g of Polycaprolactone (PCL).
(D) 5.45mg of levonorgestrel, 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25) and 0.20g of Polycaprolactone (PCL).
(E) 5.45mg of levonorgestrel, 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25) and 0.25g of Polycaprolactone (PCL).
(F) 5.45mg of levonorgestrel, 60mg of polylactic acid-glycolic acid copolymer (PLGA, 75: 25) and 0.30g of Polycaprolactone (PCL).
(II) Levonorgestrel microsphere implantation tablet in vitro release research
The 6 levonorgestrel sustained-release implant tablets in the example 3 are respectively placed in a constant-temperature water bath shaking table, the cumulative release amount (%) of the drugs at different time points is measured, and the result shows that the burst effect of the (A) is obvious, the release speeds of the (B), (C) and (D) are higher and are 30-58 days, the release speed of the (F) is low, the cumulative release amount in 90 days is 86.4%, the (D) has no burst phenomenon, the release speed is stable, the release time can reach 60-90 days, the release curve accords with a zero-order release model, and the drugs are released at a constant speed or a nearly constant speed, and the result is shown in figure 1.
In vivo pharmacokinetics study of Levonorgestrel microsphere implant
The dosage of the rat is 45mg/kg by calculation according to a conversion formula of the weight and the dosage of the rat and the human in the traditional Chinese medicine pharmacology experimental methodology. Rats were randomly divided into 3 groups of 6 rats each, and three formulations of levonorgestrel microspheres, levonorgestrel microsphere implant tablets, and commercially available levonorgestrel silica gel sticks were administered.
Levonorgestrel microspheres implant tablet groups and commercially available levonorgestrel silica gel stick groups: the rats were injected with 1% pentobarbital sodium (80mg/kg) intraperitoneally, and after anesthesia, were fixed in the supine position to maintain smooth breathing. The abdomen of the rat was shaved with scissors, and then a small incision of about 1cm in length was made in the abdomen, followed by suturing with a surgical thread after administration. And the surgical suture is wiped and disinfected by medical alcohol to avoid wound infection.
Levonorgestrel microsphere group: the levonorgestrel microspheres are administered by subcutaneous injection according to the administration dose. As the levonorgestrel is a water-insoluble drug, the microsphere powder is dissolved in physiological saline containing 2 percent of sodium carboxymethylcellulose and 1 percent of Tween-20 in an experiment, and is injected to the left subcutaneous side of the back of a rat after being fully and uniformly mixed.
The canthus blood sampling method was used to obtain blood at the prescribed time after the administration (0.5d, 1d, 2d, 3d, 6d, 9d, 16d, 23d, 30d, 37d, 44d, 51d, 58 d).
Plasma samples collected at each time point were placed in heparinized EP tubes and centrifuged at 3000rpm for 10min, and the supernatant plasma was processed as described under "2.1.4". The concentration of levonorgestrel in rat plasma after administration was determined by LC-MS/MS injection analysis and a plasma concentration-time graph 2 was plotted.
As shown in the drug-time curve chart of FIG. 2, the in vivo release curve of the levonorgestrel microspheres shows a bimodal phenomenon. The blood concentration reaches C on the 1 st day after the administrationmaxThe blood concentration is slightly reduced in 1-9 days, the blood concentration is increased to a second peak value in 9-16 days, and then the blood concentration is gradually reduced, but the blood concentration is always kept above the minimum effective contraceptive concentration (0.1ng/mL) in the whole drug release period. The levonorgestrel microsphere implant tablet has lower drug release amount than that of a microsphere group within 1 day of drug administration, the drug release behavior in the whole drug release period is similar to that of a commercially available preparation, the concentrations of the two preparations in rat plasma within 58 days are relatively stable, and the relatively obvious peak-valley fluctuation phenomenon does not exist.
Claims (9)
1. A biodegradable controlled release long-acting implant and a preparation method thereof are characterized by comprising the following components: drugs and biodegradable polymeric materials.
2. The biodegradable controlled-release long-acting implant tablet and the preparation method thereof according to claim 1, wherein; the contraceptive mainly comprises long-acting estrogen, artificially synthesized progestogen and other contraceptive medicines, preferably levonorgestrel.
3. The biodegradable controlled-release long-acting implant tablet according to claim 1, characterized in that: the levonorgestrel biodegradable polymer material consists of the following components.
4. The biodegradable controlled-release long-acting implant tablet according to claim 1, characterized in that: the biodegradable polymer comprises polylactic acid (PLA), polylactic-co-glycolic acid (PLGA) and the like, preferably the polylactic-co-glycolic acid (PLGA), wherein the ratio of the two monomers is 75: 25 or 50: 50, and the molecular weight is 20000-30000.
5. The biodegradable controlled-release long-acting implant tablet according to claim 1, characterized in that: the biodegradable polymer is Polycaprolactone (PCL) and has a molecular weight of 10000-30000.
6. The biodegradable controlled-release long-acting implant tablet according to claim 1, characterized in that: the weight percentage of the levonorgestrel in the implant is 3.8-15.6% (w/w).
7. A levonorgestrel implant according to any one of claims 1 to 4, wherein: the mass fraction of the biodegradable polymer in the implant is 84.4-96.2% (w/w).
8. The method for preparing a biodegradable controlled-release long-acting implant tablet according to claim 1, wherein: the biodegradable microsphere is prepared firstly, then the microsphere is tabletted, and finally the biodegradable material is adopted for coating.
9. The preparation method of the biodegradable controlled-release long-acting implant tablet according to claim 1 comprises the following specific steps:
1) preparation of aqueous polyvinyl alcohol (PVA) solution: adding one or more of polyvinyl alcohol-124 and polyvinyl alcohol-1788 into the water solution, swelling for 2 hr, heating in water bath for dissolving completely to obtain 0.5-3% concentration water solution of polyvinyl alcohol (PVA), and cooling to room temperature.
2) Preparing a drug-containing oil phase: adding a proper amount of ethyl acetate, tetrahydrofuran, dichloromethane, trichloromethane, acetone or a mixture of two or more solvents into polylactic acid-glycolic acid copolymers with different weight ratios to prepare a solution with the concentration of 8 mg/mL-10 mg/mL, adding 3.8-7.6% (w/w) of levonorgestrel raw material medicine, sealing, and completely dissolving by ultrasonic waves;
3) preparing biodegradable drug-loaded microspheres: the medicine carrying microsphere is prepared by adopting an O/W emulsification-solvent volatilization method. Slowly dripping the oil phase containing the medicine in the step 2) into the polyvinyl alcohol aqueous solution (PVA) in the step 1) by using an injector, and carrying out ultrasonic emulsification in an ultrasonic emulsifier at the temperature of 40.0 ℃ for 2-5 minutes to obtain O/W colostrum. Stirring or rotary evaporation is adopted to volatilize the organic solvent, and the microspheres are solidified. And then, centrifuging and washing with water to remove free drugs on the surface, and freeze-drying for 24-48 hours to obtain the drug-loaded microsphere freeze-dried powder.
4) Tablet core pressing: pressing the drug-loaded microspheres by using a single-punch tablet press to obtain a tablet core with the diameter of 6mm, wherein the tablet weight is 73.07-84.93 mg, and the ratio of the tablet thickness to the tablet diameter is 1: 3; the hardness is 2 to 3 kg.
5) Preparing a controlled-release coating solution: dissolving appropriate amount of polycaprolactone with acetone, dichloromethane, chloroform or mixture of two or more solvents; preparing polycaprolactone coating solutions with different concentrations (2%, 3%, 4%, 5% and 6%).
6) Coating of the implant: and coating the tablet core with a polycaprolactone controlled-release film, wherein the coating weight is increased by 3-5%, so as to obtain the levonorgestrel controlled-release long-acting implant tablet.
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